Breastfeeding is acknowledged as the natural and advisable way of supporting the healthy growth and development of infants due to its nutritional and immunological advantages (ESPGHAN Committee on Nutrition: Agostoni C. et al. Breast-feeding: A commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2009. 49:112-25). Breast milk provides the most suitable diet for infant's nutritional requirements. It also provides the infant with immune protection against a wide range of infection related diseases (Shulman R. J. Pediatr Res 1990. 28:171-5), and is found to provide long-term benefits in the area of certain cognitive developments. The benefits of breastfeeding are widely recognized by physicians groups including the American Academy of Pediatrics (AAP), which recommends that infants be exclusively breastfed for the first six months of life (American Academy of Pediatrics, Pediatrics, 112:e827-e841, 2012). The AAP further describes the benefits of exclusive breastfeeding as including decreased incidence of infection, gastroenteritis, obesity, and diabetes. It is also well known that the composition of human milk changes over the first few weeks following delivery of an infant. Human milk is referred to as colostrum during the first 5 days after birth, transition milk during days 6-14 after birth, and mature milk thereafter. During each stage of lactation, the corresponding human milk composition differs considerably. Colostrum and transition milk, for example, have lower caloric densities than mature milk, as well as higher protein and lower carbohydrate concentrations. Vitamin and minerals as well as hormone concentrations also vary in the three defined human milk groups. However, in the last few decades, breast-feeding has declined in all the technologically advanced societies of the world and also, even to a lesser extent, in developing countries. Many women choose not to nurse their babies at all or cease nursing after a short period of time. Others are prevented from nursing due to various medical reasons, including women suffering from certain transmissible or non-transmissible diseases, a specific example being women carrying HIV. Women that gave birth to premature babies or term babies that did not survive are also prevented from nursing.
There are many different infant nutritional formulas that are commercially available or otherwise known in the infant formula art. These infant formulae comprise a range of nutrients to meet the nutritional needs of the growing infant, and typically include lipids, carbohydrates, protein, vitamins, minerals, and other nutrients helpful for optimal infant growth and development. While an effort is made to make the commercial infant formulae similar in composition to mature human milk, they are not identical, typically due to the formula processing conditions. One of the components missing from commercial infant formulae is insulin, known to be present in its active form in maternal milk.
Observations on lactating dams and suckling rats have shown that mammalian milk insulin is biologically active, and that immature enterocytes have an increased responsiveness to the insulin (Buts J. P. et al., J Pediatr Gastroenterol Nutr 1997. 25:230-2). Insulin stimulates intestinal epithelial cell proliferation, and ileal lactase activity is increased when porcine insulin is added to feed administered to newborn piglets (Shehadeh N. et al., Pediatr Diabetes 2001. 2:175-177; Corps A. N. and Brown K. D. J Endocrinol 1987. 113:285-90). Furthermore, milk-borne insulin affects the maturation of the pancreas and induces pancreatic amylase development in rats (Kinouchi T. et al., JPGN 2000. 30:515-521). It has been previously shown that human milk insulin concentration is significantly higher (60.23±41.05 μU/ml) compared to cows' milk (16.32±5.98 μU/ml) and that insulin is hardly detected in infant formulas. The range of insulin values in human maternal milk taken 3 to 30 days after delivery was found to be between 6.45 to 305.65 μU/ml (Shehadeh N et al. 2001. Acta Paediatr 90:93-95). In additional study, it has been further evaluated whether human insulin concentration in breast milk is affected by gestational age or postnatal age. The breast milk was analyzed for insulin levels on day 3 and 10 post partum. Human milk insulin (HMI) concentration, on either day 3 or 10 post partum, was not influenced by gestational age at delivery as well as maternal age, ethnic origin, mode of delivery, weight gain in pregnancy or maternal body mass index (BMI) (Shehadeh N et al. 2003. Arch Dis Child Fetal Neonatal Ed 88:F214-F216). Insulin levels in human breast milk in mothers with type 1 and type 2 diabetes mellitus have also been studied (Whitmore T J et al. 2012 Int J Endocrinol. 2012: Article ID 296368).
Enteral insulin administration may be of benefit in reducing feeding intolerance in preterm infants (Shulman R J. Arch Dis Child Fetal Neonatal Ed. 2002. 86:F131-F133), and can suppress the development of autoimmune diabetes in mice (Schatz D. A. et al., Cleve Clin J Med 1996. 63:270-4). Orally administered insulin is usually not absorbed in the gut (Larkin M. Lancet 1997. 349:1676), and the observed effects may be local and limited to the suckling period (Shehadeh N. et al., 2001, ibid). Yet, oral insulin supplementation in non-suckling mice increases insulin serum levels and has a favorable effect on serum lipid levels, suggesting a systemic effect for insulin taken orally in this population. This is in agreement with observations in adult rats, of a transcellular (but not paracellular) intestinal transport of insulin.
While no observations were made regarding long term negative effects of oral insulin, administration of oral insulin to preterm infants from 4 to 28 days of age at a concentration as high as 4 U/kg/day, increased lactase activity and may be of benefit in reducing feeding intolerance without inducing hypoglycaemia or other adverse effects (Shulman 2002, ibid). Analyzing the effect of administered insulin on mucosal mass parameters and on expression of brush border membrane (BBM) hydrolases in a suckling rat model of immature intestine also demonstrated the safety of oral insulin given in the pharmacological range of ˜10 times higher than the estimated daily intake of milk-borne insulin demonstrating the safety of oral insulin supplementation (Buts J P et al., 1997. J Pediatr Gastroenterol Nutr 25:230-2). Furthermore, this study demonstrated that insulin is able to enhance intestinal BBM enzymes prematurely especially when given in its appropriate vehicle (rat milk).
U.S. Pat. Nos. 6,365,177 and 6,399,090 disclose an infant formula in a powder or solution form comprising nutritional components and an insulin supplement. The insulin concentration is in the range of 10 to 1000 μU/ml solution (particularly 30-100 μU/ml solution) or 83-7,500 μU/grams of powder (particularly 250-750 μU/grams of powder), and when fed to an infant the chance of the infant to develop diabetes is reduced.
U.S. Applications Publication Nos. 20070248652 and 20060147494 disclose methods for encapsulation of active ingredients, including insulin, and formulations comprising same used to enhance the health status and growth performance of human and non-human organisms.
WO 2012/052060 discloses a method for increasing the growth velocity of a human infant, particularly underweight or preterm human infants, by the enteral administration of recombinant human bile-salt-stimulated lipase (rhBSSL).
There is unmet need for infant formulae which mimics the diurnal rhythm and/or postpartum change of natural human milk, and therefore provides higher similarity to the natural components of human milk.